Treprostinil (UT15) is a class of novel drugs for treating pulmonary hypertension with the structure of formula IV:

Pulmonary arterial hypertension (PAH) is a disease mainly characterized in pulmonary arteriola vasospasm, intimal hyperplasia and remodeling. Vascular proliferation of pulmonary arteriola and remodeling will lead to progressive increase in pulmonary vascular resistance, and ultimately right ventricular failure and death.
Epoprostenol (Flolan) is the first prostacyclin drug approved by U.S. Food and Drug Administration (FDA) for treating PAH. Half-life of Epoprostenol in circulation is about 3-5 mins, continuous intravenous administration is necessary, and it should be cryopreserved before infusion.
Treprostinil is an epoprostenol analog. The compound is stable under physiological conditions, and was the first developed drug for continuous subcutaneous injection. Compared with intravenous administration of epoprostenol, subcutaneous injection of treprostinil appears safer and more convenient. Inhaled formulations thereof has also been approved by FDA.
Treprostinil was described in U.S. Pat. No. 4,306,075 for the first time. Treprostinil and other prostacyclin derivatives have been prepared according to Moriarty et al., J. Org. Chem. 2004, 69, 1890-1902, Drug of the Future, 2001, 26 (4), 364-374, U.S. Pat. Nos. 6,441,245, 6,528,688, 6,765,117, 6,809,223 and 6,756,117.
It is described in U.S. Pat. No. 5,153,222 that treprostinil is applicable to treat pulmonary hypertension. Treprostinil was approved for intravenous and subcutaneous injection, and the latter avoids continuous intravenous catheter-related sepsis events. U.S. Pat. Nos. 6,521,212 and 6,756,033 describe the treatment of pulmonary hypertension, peripheral vascular disease, as well as other diseases and symptoms by inhalation of treprostinil. U.S. Pat. No. 6,803,386 discloses the treatment of cancer by administrating treprostinil. U.S. Patent Application Publication No. 2005/0165111 discloses the treatment of ischemic lesions by using treprostinil. U.S. Pat. No. 7,199,157 discloses the improvement of renal function by using treprostinil. U.S. Patent Application Publication No. 2005/0282903 discloses the treatment of neuropathic foot ulcers by using treprostinil. U.S. application Ser. No. 12/028,471 discloses the treatment of pulmonary fibrosis by using treprostinil. U.S. Pat. No. 6,054,486 discloses the use of treprostinil for treating peripheral vascular disease. U.S. patent application Ser. No. 11/873,645 discloses a combination therapy including treprostinil. U.S. Application Publication No. 2008/0200449 discloses the delivery of treprostinil by using a dose-metered inhaler. U.S. Application Publication No. 2008/0280986 discloses the treatment of interstitial lung disease by using treprostinil. U.S. application Ser. No. 12/028,471 discloses the treatment of asthma by using treprostinil. U.S. Pat. Nos. 7,417,070, 7,384,978 and U.S. Application Publication No. 2007/0078095, 2005/0282901 and 2008/0249167 describe the oral dosage form of treprostinil and other prostacyclin analogues.
In the prior art, there are few reports regarding the crystals and purification of Treprostinil, wherein the literature (J. Org Chem 2004, 69, 1890-1902) reported a ethanol-water system for recrystallization of UT15; WO2009137066 reported a monohydrate treprostinil; and both of crystallization methods are similar and employ ethanol-water system. The inventors have prepared the crude compound I according to the method reported in the literature (J. Org. Chem. 2004, 69, 1890-1902) and obtained a slightly yellow gummy solid, however, the reaction liquids are difficult to be filtered and the residual solvent can not be completely removed under reduced pressure. Then, the obtained product was recrystallized using ethanol-water system, and dried under reduced pressure to give an extremely viscous substance. Such substance remains viscous after being stored at low-temperature (−20° C. to 0° C.), and no solidification or crystallization occurs at all.
Generally, prostaglandins have poor stability, and should be stored at less than −20° C. In view of the stability and purity of the compound, there is an urgent need in the art to obtain a stable crystal form of compound I.
